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Aim Methods Results Conclusions Patients with chronic hepatitis B (CHB) remain at risk for hepatocellular carcinoma (HCC) even with nucleos(t)ide analog therapy. We evaluated risk factors for HCC development, including serum hepatitis B virus (HBV) RNA, hepatitis B core‐related antigen level, and growth differentiation factor 15 (GDF15) level, a predictor of HCC development in patients with chronic hepatitis C.We collected clinical data and stored serum from CHB patients without a history of HCC who were receiving nucleos(t)ide analog treatment for more than 1 year and whose HBV DNA level was less than 3.0 log IU/mL. We measured the serum levels of HBV RNA and GDF15.Among 242 CHB patients, 57 had detectable HBV RNA, and GDF15 was quantified in all patients. The median GDF15 level was 0.86 ng/mL. Cox proportional hazards analysis revealed that male sex and higher GDF15, FIB‐4 index, alpha‐fetoprotein and gamma‐glutamyl transpeptidase were independent risk factors for HCC. The presence of HBV RNA above the lower limit of quantification was not a risk factor. When we set cutoff values based on the Youden index, the cumulative incidence of HCC was significantly higher in the male, AFP ≥3.0 ng/mL, gamma‐glutamyl transpeptidase ≥22 U/L, FIB‐4 index ≥1.93, and GDF‐15 ≥1.17 ng/mL groups. In patients with no or more than three of these five risk factors, the 10‐year HCC cumulative incidence rates were 0% and 41.0%, respectively.High serum GDF15 is an independent risk factor for the occurrence of HCC in CHB patients treated with nucleos(t)ide analogs. [ABSTRACT FROM AUTHOR]

Aim: Antiviral treatment reduces the risk of developing hepatocellular carcinoma (HCC) in patients with chronic hepatitis B. However, there is a lack of high‐quality evidence regarding the preventive effects of tenofovir alafenamide (TAF) on HCC. We evaluated the impact of TAF use after curative treatment on HCC recurrence. Methods: Patients who underwent surgery or radiofrequency ablation as a curative treatment for HCC were selected. Those patients who continued antiviral treatment with nucleos(t)ide analogs (NAs; entecavir [ETV] or tenofovir disoproxil fumarate [TDF]) or switched to TAF were included. The primary outcome was HCC recurrence, and the time‐varying effect of NA use on HCC recurrence was analyzed using various statistical methods. Results: Among 2794 consecutive patients with chronic hepatitis B who received curative treatment for HCC, 199 subsequently switched from ETV or TDF to TAF. After a median of 3.0 years, 1303 patients (46.6%) experienced HCC recurrence. After propensity score matching (ratio 1:10), switching to TAF was not associated with an increased HCC recurrence (HR 1.00, 95% CI 0.68–1.47; p = 1.00) by time‐varying Cox analysis. Switching to TAF was not associated with HCC recurrence in subgroups of NA (HR 1.06, 95% CI 0.67–1.67; p = 0.81 for TDF, and HR 1.09, 95% CI 0.51–2.33; p = 0.82 for ETV). Kaplan–Meier analysis showed comparable HCC recurrence‐free survival between patients who switched to TAF and those who continued with their NA (p = 0.08). Time‐varying Cox analyses in various subgroups confirmed the primary findings. Conclusions: TAF is as effective as TDF and ETV in preventing HCC recurrence after curative treatment. [ABSTRACT FROM AUTHOR]

Aim: Entecavir (ETV) and tenofovir alafenamide fumarate (TAF) are considered safe nucleoside/nucleotide analogs (NA) for the kidney. This study aimed to investigate the long‐term effects of ETV or TAF on renal function in elderly patients with chronic hepatitis B (CHB) in Japan. Methods: The study included 246 CHB patients treated with ETV (184 patients) or TAF (62 patients) for at least 2 years. These patients were divided into two groups: those <65 years of age (130 patients) and those ≥65 years of age (116 patients). The effects of the NAs on renal functions were examined by comparing the estimated glomerular filtration rates (eGFR) from baseline to 2 years between the two groups. Results: The change in eGFR from baseline to 1 or 2 years after treatment was significantly decreased in both groups. However, the amount of change at 1 and 2 years was significantly greater in the group aged ≥65 years than in the group aged <65 years. The amount of change in eGFR from baseline to 1 and 2 years after treatment was significantly greater in the group aged ≥65 years than in the group aged <65 years, regardless of the type of NA, the prior treatment history, cirrhosis/chronic hepatitis, hypertension, dyslipidemia, and diabetes. Additionally, logistic regression analysis showed that age ≥65 years was independently associated with a decreased eGFR after 2 years of NA treatment. Conclusions: Long‐term administration of NA to CHB patients over 65 years of age should be carefully monitored for renal impairment. [ABSTRACT FROM AUTHOR]

Background/Aims: Chronic hepatitis B virus (HBV) infection still poses a major threat to global health. Oligoadenylate synthetase–ribonuclease L (RNase L) antiviral pathway is one of interferon‐induced antiviral effectors. The relationship between RNase L and HBV has never been investigated and we aim to examine the serum RNase L levels in patients with different stages of chronic HBV infection. Methods: The patients were enrolled from 1985 to 2000, who had been HBsAg positive for longer than 6 months, at the National Taiwan University Hospital. In total, 426 patients with chronic HBV infection were included in this study, including 135 inactive carriers, 148 cirrhosis, and 143 hepatocellular carcinoma (HCC) cases. Results: The RNase L levels increase as the disease severity increases. Higher RNase L levels were associated with higher HBV viral load, and the HBV‐RNase L relationship was replaced by the disease severity status when adding disease status into the model. Compared with inactive carriers, the risk of liver cirrhosis was 60‐fold (odds ratio = 60.8, 95% confidence interval = 3.49–1061) with the highest quintile of RNase L levels, after the adjustment of HBV DNA. The dose–response trend was statistically significant with quintiles and one increment of RNase L level in relation to liver cirrhosis. Similar results were found when HCC was compared with inactive carriers, while there was no association when compared between liver cirrhosis and HCC. Conclusions: A positive relationship between serum RNase L and HBV viral titers or advanced disease status is uncovered in this study. Further investigation in this area may provide more details of an innate immune response for HBV and opportunity for novel therapeutic strategy. [ABSTRACT FROM AUTHOR]

Aim: Nucleos(t)ide analogs do not completely prevent hepatocellular carcinoma (HCC) in chronic hepatitis B virus infection. This study aimed to evaluate the dynamics of a non‐invasive liver fibrosis marker, the Fibrosis‐4 (FIB‐4) index, for predicting HCC development. Methods: Among a total of 882 chronically hepatitis B virus infection‐infected patients who were treated with nucleos(t)ide analogs, 472 patients without HCC history whose FIB‐4 at baseline and 1 year of treatment was obtained were evaluated for the incidence of HCC. Results: The median FIB‐4 was 2.00 at baseline and was significantly reduced to 1.58 at 1 year (P < 0.001), but the reduction was small at 2 years or later. When a receiver operating characteristic analysis of FIB‐4 was performed to predict HCC within 5 years, the area under the curve of FIB‐4 at 1 year was higher than that at baseline (0.676 vs. 0.599). The HCC incidence was significantly higher in patients with FIB‐4 ≥1.58 than in those with FIB‐4 <1.58 (14.8% vs. 3.6% at 10 years, P < 0.001). Additionally, an abnormal alanine aminotransferase (≥31 U/L) at 1 year was an independent risk for HCC. When a fibrosis and alanine aminotransferase‐1 (FAL‐1) score was evaluated as an applicable number of FIB‐4 ≥1.58, and alanine aminotransferase ≥31 as 0, 1, and 2, the HCC risk in patients with score 2 was significantly higher than in those with score 1 or score 0 (24.1% vs. 9.8% vs. 0.7% at 10 years, P < 0.001). Conclusions: FIB‐4 ≥1.58 and alanine aminotransferase ≥31 at 1 year of nucleos(t)ide analog was an independent risk factor for HCC development, and a score using these factors stratified the risk of HCC. [ABSTRACT FROM AUTHOR]

Aim: To weight the prognostic value of thyroid hormones in catastrophic acute‐on‐chronic liver failure (ACLF). Methods: A retrospective cohort (n = 635) and two prospective cohorts (n = 353, and 198) were enrolled in this study. The performance of a novel developed prognostic score was assessed from aspects of reliability, discrimination, and clinical net benefit. Results: Thyroid‐stimulating hormone (TSH) was identified to have the most potential as a prognostic predictor for hepatitis B virus‐related ACLF among thyroid hormones. The novel score (modified chronic liver failure–organ failure score [mCLIF‐OFs]) was developed with weighted TSH and other scored organs in the CLIF‐OFs using the retrospective cohort (n = 635). The predicted risk and observed probabilities of death were comparable across the deciles of mCLIF‐OFs (Hosmer–Lemeshow χ2 = 4.28, p = 0.83; Brier scaled = 11.9). The C‐index of mCLIF‐OFs (0.885 [0.883–0.887]) for 30‐day mortality was significantly higher than that of the CLIF‐OFs, chronic liver failure–sequential organ failure assessment score (CLIF‐SOFAs), CLIF‐C ACLFs, Model of End‐stage Liver Disease (MELD), and Child–Pugh (all p < 0.001). The absolute improvements of prediction error rates of the mCLIF‐OFs compared to the above five scores were from 19.0% to 61.1%. After the analysis of probability density function, the mCLIF‐OFs showed the least overlapping coefficients (27.9%) among the above prognostic scores. Additionally, the mCLIF‐OFs showed greater net benefit than the above five prognostic scores over a wide range of risk threshold of death. Similar results were validated in two prospective ACLF cohorts with HBV and non‐HBV etiologies. Conclusion: Weighted TSH portended the outcome of ACLF patients, which could be treated as a "damaged organ" of the hypothalamic–pituitary–thyroid axis. The novel mCLIF‐OFs is a reliable prognostic score with better discrimination power and clinical net benefit than CLIF‐OFs, CLIF‐SOFAs, CLIF‐C ACLFs, MELD, and Child–Pugh. [ABSTRACT FROM AUTHOR]

Aim: This study aimed to evaluate the cost‐effectiveness of hepatitis E vaccination strategies in chronic hepatitis B (CHB) patients. Methods: Based on the societal perspective, the cost‐effectiveness of three hepatitis E vaccination strategies—vaccination without screening, screening‐based vaccination, and no vaccination—among CHB patients was evaluated using a decision tree–Markov model, and incremental cost‐effectiveness ratios (ICERs) were calculated. Values for treatment costs and health utilities were estimated from a prior investigation on disease burden, and values for transition probabilities and vaccination‐related costs were obtained from previous studies and government agencies. Sensitivity analyses were undertaken for assessing model uncertainties. Results: It was estimated that CHB patients superinfected with hepatitis E virus (HEV) incurred significantly longer disease course, higher economic burden, and more health loss compared to those with HEV infection alone (all p < 0.05). The ICERs of vaccination without screening and screening‐based vaccination compared to no vaccination were 41,843.01 yuan/quality‐adjusted life year (QALY) and 29,147.32 yuan/QALY, respectively, both lower than China's per‐capita gross domestic product (GDP) in 2018. The screening‐based vaccination reduced the cost and gained more QALYs than vaccination without screening. One‐way sensitivity analyses revealed that vaccine price, vaccine protection rate, and decay rate of vaccine protection had the greatest impact on the cost‐effectiveness analysis. Probabilistic sensitivity analyses confirmed the base‐case results, and if the willingness‐to‐pay value reached per‐capita GDP, the probability that screening‐based vaccination would be cost‐effective was approaching 100%. Conclusions: The disease burden in CHB patients superinfected with HEV is relatively heavy in China, and the screening‐based hepatitis E vaccination strategy for CHB patients is the most cost‐effective option. [ABSTRACT FROM AUTHOR]

Aim: Interleukin (IL)‐10 and IL‐12 contribute to immune responses against hepatitis B virus (HBV) infection. Polymorphisms in the IL‐10 and IL‐12A genes might affect the clinical outcome of HBV infection. We evaluated the association of IL‐10 rs1800896 and rs3024490, and IL‐12A rs568408 and rs2243115 with the progression of HBV infection and development of severe liver disease stages in a white European population. Method: A total of 636 white European patients with chronic HBV infection, 239 individuals with spontaneous HBV surface antigen seroclearance, and 254 healthy controls were enrolled. The chronic HBV infection group included patients with hepatitis B envelope antigen (HBeAg) negative chronic hepatitis B (n = 255), with HBeAg positive chronic hepatitis B (n = 99) and with HBeAg negative HBV infection (n = 228). A total of 104 chronically infected patients were diagnosed with liver cirrhosis. Serum levels of cytokines were measured in patients with HBV infection (n = 195) and in healthy controls (n = 160). Results: In adjusted multivariate analysis, the IL‐10 rs1800896 AG/GG genotypes were significantly associated with an increased probability of HBV surface antigen seroclearance (OR = 1.75, 95% CI 1.04–2.94, p = 0.034), with an increased likelihood of HBeAg negative chronic infection (OR = 1.93, 95% CI 1.05–3.54, p = 0.034) and with increased serum cytokines levels in female patients. In contrast, the IL‐12A rs568408 AG/AA genotypes were independently associated with an increased risk to develop liver cirrhosis, with an OR of 1.90 (95% CI 1.07–3.39, p = 0.029) in male patients. Conclusion: The current study shows a sex‐related association of the IL‐10 single‐nucleotide polymorphism rs1800896 and IL‐12A single‐nucleotide polymorphism rs568408 with different stages of HBV infection and with HBV‐related liver cirrhosis in white European patients. [ABSTRACT FROM AUTHOR]

Aim: Reports of patients with hepatitis B have highlighted associations between polymorphisms in the human leukocyte antigen (HLA)‐DPB1, CXCL13, and CXCR5 genes and disease pathology. Owing to its potential to contribute to the development of new diagnostic and therapeutic methods, we aimed to establish a reliable host genome analysis technique that can be used in countries with inadequate infrastructure. Method: We compared multiple commercially available kits for dried blood spot (DBS)‐based sample collection to develop a basic DBS‐based host genome analysis technique. We then collected blood samples from Cambodian patients with hepatitis B and performed single‐nucleotide polymorphism genotyping and HLA allele typing by the DBS system. Result: We were able to perform single‐nucleotide polymorphism genotyping and HLA allele typing with host DNA samples obtained using a combination of a HemaSpot™ filter paper‐based device and a SMITEST® EX‐R&D DNA extraction kit. The accuracy of genotyping using samples obtained by this method was not inferior to one using samples obtained by venipuncture. In the Cambodian population, significant associations of HLA‐DPB1*04:01 with protection against chronic hepatitis B virus (HBV) infection, and HLA‐DPB1*05:01 and HLA‐DPB1*13:01 with susceptibility to chronic HBV infection were identified. Conclusion: Based on the DBS system, we clarified the associations of HLA‐DPB1 alleles with chronic HBV infection in the Cambodian population for the first time. Because the DBS is a low‐cost, durable, transportable, and easy‐to‐handle modality, genetic analysis based on the DBS system is a feasible strategy for obtaining a deeper understanding of HBV epidemiology, especially in middle‐ or low‐income countries. [ABSTRACT FROM AUTHOR]

This article discusses the cost-effectiveness of hepatitis E virus (HEV) vaccination strategies among patients with chronic hepatitis B (CHB) in China. Hepatitis E is a leading cause of acute viral hepatitis worldwide, with millions of infections and thousands of deaths each year. Certain populations, such as those with advanced chronic liver disease, pregnant women, and immunocompromised patients, are at particular risk of severe outcomes from HEV infection. The article highlights the development of the HEV 239 vaccine and concludes that a screening-based vaccination strategy for CHB patients is the most cost-effective option. The authors emphasize the importance of region-specific vaccination strategies based on HEV endemicity. [Extracted from the article]

Background: Immunosuppression in a tumor microenvironment is associated with enhanced tumor progression. Natural killer group 2 (NKG2) family proteins, including inhibitory receptors and activators, can be used as attractive targets for immunotherapy of immune checkpoint inhibition. We further explore the expression level prognostic value of NKG2A and NKG2D in hepatitis B virus‐related hepatocellular carcinoma (HBV‐HCC). Methods: This study was a prospective study involving 92 patients with HBV‐HCC, 16 patients with HBV‐related liver cirrhosis, 18 patients with CHB, and 38 healthy donors. We analyzed the expression and related functions of NKG2A, NKG2D, and the NKG2A/NKG2D ratio in the peripheral blood of patients with HBV‐HCC and analyzed tumor progression. The tissue samples from patients with HBV‐HCC were further used for multiple immunofluorescence and immunohistochemistry. Results: In patients with HBV‐HCC with tumor progression, the ratio of NKG2A/NKG2D is higher in NK cells and T cells. The Kaplan–Meier survival curve showed that the NKG2A/NKG2D ratio on NK cells could predict tumor progression in patients with HBV‐HCC, and that an increase in this ratio was associated with inhibition of NK cell function. The Cancer Genome Atlas (TCGA) database was further used to verify that the higher the NKG2A/NKG2D ratio, the shorter the progression‐free survival of patients with HCC, and the more likely the immune function was suppressed. Conclusions: The imbalance between NKG2A and NKG2D of NK cells is involved in NK cell immunosuppression, and the increase of the NKG2A/NKG2D ratio is related to the tumor progression of HBV‐HCC. [ABSTRACT FROM AUTHOR]

Background: The clinical features have been well described in obese chronic hepatitis B (CHB) patients with nonalcoholic fatty liver disease (NAFLD). However, little is known about the clinical features of lean CHB‐NAFLD patients. Methods: The study retrospectively included treatment‐naïve CHB patients who underwent ultrasound between 2015 and 2021. Liver fibrosis was assessed by aspartate aminotransferase (AST) to platelet ratio index (APRI), Fibrosis‐4 score (FIB‐4), NAFLD fibrosis score (NFS), and transient elastography. Results: Among 1226 CHB‐NAFLD patients, 25.0% patients were lean. The age, gender, and platelet, alanine aminotransferase, AST, and albumin levels were comparable between lean CHB‐NAFLD and nonlean patients. The levels of plasma glucose, triglycerides, total cholesterol, and uric acid, as well as proportions of concurrent hypertension and diabetes, were lower in lean patients. Lean patients presented higher hepatitis B surface antigen (HBsAg) levels (3.4 log10 IU/ml vs. 3.2 log10 IU/ml, p = 0.006), hepatitis B virus (HBV) DNA levels (4.1 log10 IU/ml vs. 3.2 log10 IU/ml, p < 0.001), and hepatitis B e antigen (HBeAg) positive proportions (40.4% vs. 30.2%, p = 0.002) than nonlean patients. The values of APRI, FIB‐4, and liver stiffness were comparable between two groups. However, lean patients had lower NFS values (−3.0 vs. −2.6, p < 0.001) and lower proportions (12.6% vs. 21.1%, p = 0.003) of advanced fibrosis (NFS ≥ −1.5) than nonlean patients. Similar results were observed in HBeAg‐positive and HBeAg‐negative subgroups. Conclusions: Nearly a quarter of CHB‐NAFLD patients were lean. Lean patients had lower proportions of metabolic abnormalities and advanced liver fibrosis than nonlean patients. However, lean CHB‐NAFLD patients had higher HBsAg levels, HBV DNA levels, and HBeAg‐positive proportions. Registry and registration no. of the study/trial: Clinicaltrials.gov, Identifier: NCT03097952. [ABSTRACT FROM AUTHOR]

Aims: HBsAg loss with anti‐HBs acquisition is considered a functional cure and ideal treatment goal for patients with CHB. Our group have reported the efficacy of therapeutic vaccine with HBsAg and HBcAg (NASVAC) by intranasal and subcutaneous injection. In this study, we investigated the safety and efficacy of newly developed CVP‐NASVAC, which contained NASVAC with mucoadhesive carboxyl vinyl polymer (CVP) in the dedicated device. Methods: A single dose, open‐label, phase IIa clinical trial of CVP‐NASVAC was conducted. Patients with CHB treated with nucleoside/nucleotide analogs (NAs) and HBV carriers not undergoing anti‐HBV treatment were enrolled. CVP‐NASVAC was injected through the nose for, in total, 10 times. Participants were followed‐up for 18 months, and their HBsAg reduction and anti‐HBs induction assessed as endpoints. Results: Among the patients with CHB treated with NAs (n = 27) and HBV carriers without NAs (n = 36), 74.1% and 75.0% exhibited reductions in their baseline HBsAg, and the mean reductions were −0.1454 log10 IU/ml (p < 0.05) and −0.2677 log10 IU/ml (p < 0.05), respectively. Anti‐HBs antibody was detected in 40.7% and 58.3% of patients treated with and without NAs, respectively. Six of 71 (9.5%) patients were functionally cured after the CVP‐NASVAC treatment. Conclusions: Anti‐HBs induction and HBsAg reduction was observed after CVP‐NASVAC treatment in some patients with CHB. The CVP‐NASVAC is a safe treatment, which might expect to achieve functional cure for patients with CHB. [ABSTRACT FROM AUTHOR]

Aim: Alanine aminotransferase (ALT) is a criterion for the introduction of nucleotide/nucleoside analog (NA), and ALT levels are decreased by NA treatment. However, the association between post‐treatment ALT levels and hepatocellular carcinoma (HCC) risk remains unclear. To fill this gap, we aimed to establish a target value of ALT level during NA treatment. Methods: In total, 413 patients with chronic hepatitis B who received entecavir, tenofovir alafenamide, or tenofovir disoproxil fumarate were enrolled. The subsequent development of HCC was examined and a target value of ALT level during NA treatment as a risk marker for HCC was evaluated. Results: The median follow‐up duration was 5.1 years, during which time 27 patients (8.6%) developed HCC. ALT level at the start of treatment was not associated with HCC development (p = 0.08). When stratified by ALT at 1 year after NA initiation, the cumulative 3‐ and 5‐year rates of HCC for patients with ALT ≥21 IU/L were 11.5% and 18.1%, and those with ALT <21 IU/L was 2.3% and 6.5%, respectively. Patients with ALT <21 IU/L had a significantly lower risk of HCC development compared with patients with ALT ≥21 IU/L (p = 0.002). In multivariable analysis adjusting age, sex, and platelet counts, ALT ≥21 IU/L was an independent risk factor of HCC development with hazard ratio of 4.5 (95% confidence interval: 1.01–20.4). Conclusions: ALT <21 IU/L at 1 year after NA initiation has a lower risk of HCC and could be used as a target value for NA treatment. [ABSTRACT FROM AUTHOR]

Background: The association between metabolic dysfunction‐associated fatty liver disease (MAFLD) and hepatocellular carcinoma (HCC) lacks clinical validation in at‐risk populations. We assessed this relationship among chronic hepatitis B (CHB) patients. Methods: Data was collected from the National Health Insurance System database in South Korea. Chronic hepatitis B patients aged over 40 years receiving health examinations between 2011 and 2012 were recruited. The primary outcome was HCC. Metabolic dysfunction‐associated fatty liver disease was defined as hepatic steatosis in combination with at least one of the following: (i) overweight, (ii) diabetes, or (iii) lean/normal weight with two or more metabolic components. Multivariable Cox regression analysis was used to estimate adjusted hazard ratios (aHRs). Results: Of 197 346 participants, 66 149 had MAFLD; 19 149, 44 475, and 2525 fulfilled diabetes (regardless of overweight), overweight alone, and lean/normal weight with two or more metabolic components, respectively. During follow‐up (median 7 years), 13 771 developed HCC. Metabolic dysfunction‐associated fatty liver disease was independently associated with increased risk of HCC, with aHR of 1.36 (p < 0.001). Propensity score matching confirmed the same phenomena, with aHR of 1.37 (p < 0.001). Furthermore, when stratified by liver cirrhosis and/or antiviral therapy, independent significances of MAFLD for HCC risk were maintained (all p < 0.001). Compared with the persistent non‐MAFLD subgroup during the entire follow‐up, diagnosis of MAFLD from at least one health examination significantly increased HCC risk with aHRs of 1.41, 1.37, and 1.14 among subgroups with persistent MAFLD, MAFLD to non‐MAFLD, and non‐MAFLD to MAFLD, respectively (all p < 0.05). Conclusions: Metabolic dysfunction‐associated fatty liver disease consistently increases HCC risk among CHB patients. Further studies are needed to develop an effective preventive strategy through control of metabolic health. [ABSTRACT FROM AUTHOR]

Aim: Hepatitis B flare has been interpreted as result of immune response against upsurging hepatitis B virus (HBV) and its antigen(s) that may lead to HBV decline/clearance spontaneously. It has been speculated that antiviral therapy could halt the effective immune response with viral persistent as a consequence. A proof‐of‐concept study was conducted to investigate this issue. Methods: Serial biochemical, quantitative hepatitis B surface antigen (HBsAg), interferon‐γ (IFN‐γ) and tumor‐necrosis factor‐α (TNF‐α) assays were performed in four patients with severe hepatitis flare who had achieved precipitous HBsAg decline within 4 weeks of antiviral therapy. Results: TNF‐α and IFN‐γ were found to be elevated in parallel to upsurging HBV DNA and HBsAg levels in all patients. Higher levels of TNF‐α and IFN‐γ and levels relative to qHBsAg were observed during and after early termination of therapy within 4 weeks in two patients and were followed by further HBsAg decline to <5 IU/ml and even achieved HBsAg loss in one patient. The patient who had stopped therapy on day 44 showed minimal HBsAg decline afterward and the patient who continued therapy showed a 10‐fold rebound of qHBsAg from its nadir. The subsequent IFN‐γ and TNF‐α activity of these two patients was minimal. Conclusions: The results suggest that patients with severe hepatitis flare who achieved precipitous HBsAg decline may have robust immune response to clear the virus, and early termination of antiviral therapy may allow the protective immune response to continue and accelerate HBV decline toward HBsAg loss. [ABSTRACT FROM AUTHOR]

Aim: The risk of hepatitis B virus (HBV) reactivation with immune checkpoint inhibitors (ICIs) is an important issue that has not yet been fully investigated. ICI is also expected to have an antiviral effect on HBV due to its immune tolerance inhibitory effect. We herein investigated the risk of HBV reactivation and the antiviral effect of ICI administration. Methods: This study included 892 patients on ICIs between September 2014 and May 2021 at our hospital. The frequency of HBV reactivation and antiviral effects were investigated. Results: Among the 892 patients who underwent ICI, 27 were hepatitis B surface antigen (HBsAg) positive. HBV reactivation was evaluated in 24 cases, among which 4.1% (1/24) had HBV reactivation. Nucleic acid analog prophylaxis was not administered to patients with reactivation. In a study of 15 cases, the amount of HBsAg decreased from baseline; 2.18 ± 0.77 log to 48 weeks later; 1.61 ± 1.38 log (p = 0.17). Forty‐eight weeks after the start of ICI, disappearance of HBsAg was observed in two out of 15 cases (13.3%), and one case each with and without nucleic acid analog. Conclusion: In rare cases, HBsAg‐positive patients may be reactivated by ICI administration. On the other hand, when ICI is administered, it is expected to have an antiviral effect on HBV due to its immune tolerance inhibitory effect, and future drug development is expected. [ABSTRACT FROM AUTHOR]

Background & Aims: Benefits of nucleos(t)ide analogs (NAs) on hepatitis B surface antigen (HBsAg) reduction and interferon‐lambda3 (IFN‐λ3) induction are still not known. This study aimed to investigate the effects of NAs on HBsAg reduction and association with serum IFN‐λ3 levels in chronic hepatitis B (CHB) patients. Methods: A total of 91 patients [51 treated with nucleoside analog entecavir hydrate (ETV) and 40 treated with nucleotide analog adefovir dipivoxil (ADV) or tenofovir disoproxil fumarate (TDF)] with clinically evident CHB (chronic hepatitis, 57; liver cirrhosis, 34) were enrolled in this study. Serum IFN‐λ3 levels among patients receiving ETV and ADV/TDF were measured before the initiation of therapy and 1, 3, and 5 years post‐therapy. Results: The change (mean ± standard deviation) in serum HBsAg levels from baseline to year five was −0.38 ± 0.46 and −0.84 ± 0.64 log10 IU/ml in ETV and ADV/TDF groups, respectively (p = 0.0004). Higher serum IFN‐λ3 levels were observed in ADV/TDF group compared with ETV group during treatment (p < 0.001). Serum IFN‐λ3 levels showed negative correlation with HBsAg reduction in ADV/TDF group (r = −0.386, p = 0.038) at week 48. Nucleotide analogs (ADV/TDF) treatment has associated factors with −0.3 log HBsAg decline at 1 year, −0.5 log HBsAg decline at 3 years, and −0.8 log HBsAg decline at 5 years after NAs treatment on multivariate analysis. Conclusions: Nucleotide analog (ADV/TDF) treatment reduced HBsAg levels greater compared with nucleoside analog (ETV) in parallel with IFN‐λ3 induction. [ABSTRACT FROM AUTHOR]

A study published in Hepatology Research explores the relationship between the ribonuclease RNase-L and hepatitis B virus (HBV) infection. The researchers found a positive correlation between RNase-L levels and HBV viral titers in patients with chronic HBV infection. Higher levels of RNase-L were identified as a potential risk factor for cirrhosis. The study suggests that serum RNase-L levels could serve as a biomarker to stratify the stage of chronic hepatitis B disease, although further investigation is needed to fully understand the relationship between RNase-L and HBV. [Extracted from the article]

A study published in Hepatology Research examined the Fibrosis-4 (FIB-4) index as a tool for predicting the risk of hepatocellular carcinoma (HCC) in patients with chronic hepatitis B undergoing nucleos(t)ide analog (NA) therapy. The study found that elevated FIB-4 levels after 1 year of NA therapy were independent risk factors for HCC development. The study also introduced the FAL-1 score, which combines FIB-4 and alanine aminotransferase (ALT) levels to categorize patients into three groups based on HCC risk. The study emphasized the importance of individualized patient assessment and regular monitoring for early detection of HCC. Another study highlighted the role of the Chinese University-HCC (CU-HCC) score in predicting HCC risk in patients undergoing antiviral therapy. Both studies emphasized the significance of ALT levels and the 1-year mark of treatment in assessing HCC risk. The findings underscored the dual nature of the FIB-4 index, indicating both inflammation and fibrosis, and the need for personalized patient assessment before initiating NA treatment. [Extracted from the article]

Aim: To summarize HBV‐related biomarkers predicting nucleos(t)ide analogs (NAs) discontinuation and hepatitis B virus (HBV) recurrence after drug withdrawal in chronic hepatitis B (CHB) patients, providing references for clinical medication, so as to manage CHB patients more scientifically. Methods: Related pieces of literature were retrieved in PubMed and the results were sorted out. We then analyzed and summarized these articles. Results: We found that HBV related biomarkers maybe could predict NAs withdrawal safely and the possibility of relapse after treatment cessation, including hepatitis B e antigen (HBeAg), hepatitis B surface antigen (HBsAg), HBV DNA, HBV RNA, pregenomic‐RNA (pgRNA), hepatitis B core‐related antigen (HBcrAg), hepatitis B core antibody (anti‐HBc), and models containing several indicators for predicting the effectiveness of treatment. Conclusions: HBV DNA, HBV RNA, pgRNA, HBcrAg, anti‐HBc, as well as the prediction models formed by several biomarkers could predict the safe discontinuation of NAs before HBsAg loss and recurrence. [ABSTRACT FROM AUTHOR]

The article focuses on evaluating the predictive value of hepatitis B surface antigen glycan isomer (HBsAgGi) in relation to the development of hepatocellular carcinoma (HCC) during nucleoside/nucleotide analog (NA) therapy. It critiques a study by Kozuka et al. for potential statistical issues in their analysis methodology, suggesting improvements to enhance the reliability of predictor results.

Background: Long‐term use of nucleotide analogs such as adefovir (ADV) or tenofovir disoproxil fumarate (TDF) may cause renal impairment. Tenofovir alafenamide (TAF) has less systemic exposure than TDF did. The aims were to examine longitudinal changes in renal function and biochemical parameters for 2 years after switching from long‐term ADV and TDF to TAF, and to explore factors associated with improved renal function after TAF in patients with chronic hepatitis B. Methods: The prospective observational cohort study included 306 patients with chronic hepatitis B who underwent switching from long‐term TDF or ADV to TAF. The primary outcome was the changes in estimated glomerular filtration rate (eGFR) after TAF. Results: Among 306 patients, 190 (65.3%) and 106 (34.7%) had chronic kidney disease (CKD) stages 1–2 and 3a–4 at baseline. In patients with CKD stages 3a–4, the mean eGFR significantly increased until week 12 and plateaued from week 12 to year 2 (adjusted slope using linear mixed effect models: +9.01 ml/min/1.73 m2/year until week 12; p < 0.001). In contrast, the mean eGFR plateaued from baseline to year 2 in the CKD stages 1–2 subgroup. Multivariate logistic regression showed that baseline CKD stage ≥3a, steeper decline in eGFR 1 year before TAF, and shorter duration of any nucleotide analog use was significantly associated with ≥10% improvement in eGFR in year 1. Conclusions: Switching from TDF or ADV to TAF resulted in favorable renal safety for 2 years. In CKD stage 3a–4 subgroup, eGFR after TAF was recovered in the first 12 weeks and subsequently stabilized. [ABSTRACT FROM AUTHOR]

Aims: This study aimed to evaluate the clinical usefulness of the aminotransferase to platelet ratio index (APRI), fibrosis‐4 (FIB‐4), and modified FIB‐4 (mFIB‐4) indices in predicting hepatocellular carcinoma (HCC) in patients receiving entecavir (ETV) treatment. Methods: Among 1955 patients treated with ETV, a total of 857 treatment‐naive chronic hepatitis B patients (424 with liver cirrhosis [LC], 433 without cirrhosis) treated with ETV for more than 1 year were analyzed. Results: Of the 857 patients, 85 (9.9%) patients (77 in the LC group and 8 in the non‐LC group) developed HCC during the follow‐up period. The median observation period was 6.9 years. Multivariate regression analysis of HCC incidence revealed that the initial mFIB‐4 index (hazard ratio [HR] 1.058; 95% confidence interval [CI], 1.007–1.112; p = 0.027) and improvement in the FIB‐4 index after 1 year of ETV treatment (HR 0.531; 95% CI, 0.339–0.831; p = 0.006) were independent prognostic factors in the entire cohort. In the LC group, the improvement of the FIB‐4 index following ETV treatment (HR 0.491; 95% CI, 0.280–0.861; p = 0.013) was negatively correlated with incidence of HCC. However, the area under the receiver operating characteristic curve of specific cut‐off values of the FIB‐4 index at baseline and 1 year after ETV treatment were 0.572 (95% CI, 0.504–0.640) and 0.615 (95% CI, 0.546–0.684), respectively. In the non‐LC group, none of the invasive fibrosis indices could predict HCC incidence. Conclusions: The specific cut‐off value of the FIB‐4 index was not suitable for predicting HCC. However, the improvement in the FIB‐4 index after 1 year of ETV therapy could be a predictor of HCC development in cirrhotic patients. [ABSTRACT FROM AUTHOR]

Aim: Both entecavir (ETV) and tenofovir alafenamide fumarate (TAF) are widely used to treat chronic hepatitis B (CHB) in Japan. However, it remains unclear whether the efficacy of TAF in decreasing the hepatitis B surface antigen (HBsAg) level, and its safety, are superior to those of ETV. This study aimed to report the long‐term effects and safety of 96‐week ETV and TAF treatment in patients with CHB. Methods: A prospective comparative observational study was undertaken on the following two groups: patients with CHB who received continuous ETV (n = 32) and patients with CHB who were switched from ETV to TAF upon request (n = 48). The HBsAg, urinary β2‐microglobulin (β2MG)/creatinine (Cr), urinary N‐acetyl‐β‐D‐glucosaminidase (NAG)/Cr, and serum alanine aminotransferase (ALT) levels, estimated glomerular filtration rate (eGFR), and bone mineral density (lumbar spine and femur) at 96 weeks were compared. Results: The two groups did not significantly differ with respect to mean age, male / female patient ratio, or rate of hepatitis B e antigen‐positive status. The mean changes in serum HBsAg level and eGFR at 96 weeks were not significantly different between the two groups. The β2MG/Cr and NAG/Cr levels at 96 weeks were similar between the two groups. Additionally, the bone mineral density of the lumbar spine and femur as well as the serum ALT did not significantly differ. Conclusions: When compared with patients who received continuous ETV, those who were introduced to TAF after ETV showed similar effects in terms of the decrease in HBsAg level and safety. [ABSTRACT FROM AUTHOR]

Aim: To assess the role of consolidation therapy after cessation of nucleoside/nucleotide analogs (NAs) for off‐treatment outcome and to explore the optimal consolidation period in hepatitis B e‐antigen (HBeAg) positive chronic hepatitis B (CHB) patients. Methods: We undertook a prospective, observational cohort study including HBeAg positive CHB patients discontinuing NAs. Virological relapse was the primary endpoint of the current study and was defined as a serum hepatitis B virus DNA more than 104 copies/ml (another assay was carried out for confirmation at least 2 weeks later). Propensity score matching analysis was used to balance the baseline characteristics between HBeAg positive CHB patients with different consolidation periods. Results: A total of 190 HBeAg positive CHB patients were included. Fifty‐four patients relapsed during follow‐up and the cumulative relapse rates at years 1, 3, 5, and 10 were 19.5%, 24.1%, 27.2%, and 32.1%, respectively. Most patients (61.1%) relapsed in the first 6 months. After propensity score matching, significantly lower cumulative relapse rates were observed in patients with consolidation period ≥36 months compared with patients with consolidation period more than 36 months (29.3% vs. 52.8% at year 10; p = 0.012). Conclusions: Cessation of NAs after HBeAg seroconversion and long‐term consolidation is generally safe and feasible in HBeAg positive CHB patients. Three years of consolidation should be preferred in clinical practice. [ABSTRACT FROM AUTHOR]

Aim: Risk prediction models for hepatocellular carcinoma (HCC) development are available. However, the influence of antiviral therapy (AVT) on these models in patients with chronic hepatitis B is unknown. Methods: The dynamic changes in risk prediction models during AVT and the association between risk prediction model and the risk of chronic hepatitis B‐related HCC development were investigated. Between 2005 and 2017, 4917 patients with chronic hepatitis B (3361 noncirrhotic, 1556 cirrhotic) were recruited. Results: The mean age of the study population was 49.3 years and 60.6% (n = 2980) of the patients were male. The mean Chinese University‐HCC (CU‐HCC) score was 12.7 at baseline in the overall study population, and decreased significantly (mean, 8.7) after 1 year of AVT (p < 0.001). The score was maintained throughout 5 years of AVT (mean, 8.4–8.8; p > 0.05). The proportion of high‐risk patients (CU‐HCC score ≥ 20) was 28.9% at baseline, and decreased significantly after 1 year of AVT (5.0%; p < 0.001), and remained stable through 5 years of AVT (2.2%–3.6%; p > 0.05). In addition to the score at baseline, the CU‐HCC score at 1 year of AVT independently predicted the risk of HCC development (hazard ratio = 1.072; p < 0.001), together with male gender and platelet count (all p < 0.05). Conclusions: The CU‐HCC score significantly decreased at 1 year of AVT and was maintained thereafter. The CU‐HCC score after 1 year of AVT independently predicted the risk of HCC development in patients with chronic hepatitis B. [ABSTRACT FROM AUTHOR]

Tenofovir disoproxil fumarate (TDF) is widely used to treat hepatitis B virus (HBV) patients worldwide. We previously reported a patient with CHB and cirrhosis in whom viral breakthrough occurred during combination therapy with TDF and entecavir (ETV) against ETV‐resistant virus. A recent Korean report showed that two patients with viral breakthrough during treatment with TDF‐containing regimens were found to carry five reverse transcriptase (rt) mutations ([rt]S106C[C], rtH126Y[Y], rtD134E[E], rtM204I/V, and rtL269I [I]), with the C, Y, E, and I mutations being associated with tenofovir resistance. We report the clinical course up to September 2019 in our patient, and compare the HBV mutations to those of the two Korean patients. Four mutations (rtS106C, rtD134N/S[N/S], rtM204V, and rtL269I) plus ETV resistance (rtL180M and rtS202G) existed when she developed viral breakthrough during ETV and TDF combination therapy in April 2013. Moreover, three mutations (rtS106C, rtD134N, and rtL269I) existed at baseline. Our patient's father is Korean. Considering these factors, patients with these three or four mutations (CYEI or CN/SI) at baseline could experience tenofovir resistance in addition to lamivudine (LAM) or ETV resistance. In addition, HBV DNA levels fluctuated during tenofovir alafenamide (TAF) and LAM therapy in our patient, although treatment was switched from LAM, TDF, and ETV to LAM and TAF combination therapy in April 2018. In conclusion, three mutations (CN/SI) plus ETV resistance (rtL180M, rtM204V, and rtS202G) can cause tenofovir resistance. Long‐term therapy with tenofovir against ETV‐resistant virus has the potential to induce viral breakthrough and resistance, necessitating careful follow‐up. [ABSTRACT FROM AUTHOR]

Aims: Hepatitis B surface antigen (HBsAg) seroclearance indicates a "functional cure" in chronic hepatitis B (CHB) virus infection. However, several cases of hepatocellular carcinoma (HCC) development have been reported after HBsAg seroclearance. We evaluated the potential of HBsAg and hepatitis B core‐related antigen (HBcrAg), measured by the ultra‐highly sensitive assays, in cases with HCC development after HBsAg seroclearance. Methods: We enrolled 17 patients with CHB who achieved HBsAg seroclearance, defined by the conventional assay using Architect HBsAg QT kit (five HCC patients and 12 non‐HCC patients). HBsAg and HBcrAg were measured in their stored serum samples using ultra‐highly sensitive assays featuring "immunoassay for total antigen including complex via pretreatment (iTACT)" technology. Results: All five patients who developed HCC were positive for HBsAg or HBcrAg by iTACT‐HBsAg or iTACT‐HBcrAg at all follow‐up points. HBcrAg levels in the HCC group, using iTACT‐HBcrAg, were significantly higher than those in the non‐HCC group at HBsAg seroclearance (3.6 LogU/ml (2.8–4.2) versus 2.6 (<2.1–3.8), p = 0.020). The best cutoff value of iTACT‐HBcrAg for predicting HCC development was 2.7 LogU/ml by receiver operating characteristic curve analysis. The prevalence of HBcrAg ≥2.7 in the HCC group was significantly higher than that in non‐HCC group (100% [5/5] versus 33% [4/12], p = 0.029). Conclusions: Residual low viral antigen might predict HCC development even if HBsAg seroclearance was achieved according to a conventional assay. The results suggest that iTACT assays of HBsAg and HBcrAg would be useful for monitoring CHB patients. [ABSTRACT FROM AUTHOR]

Aim: Recently, serum hepatitis B virus (HBV)‐RNA has been reported to be detectable even when HBV particle production is inhibited by nucleot(s)ide analogues (NAs). However, the dynamics of the HBV‐RNA sequence compared with those of HBV‐DNA during the emergence of antiviral resistance are yet to be elucidated. Methods: First, we quantified serum HBV‐RNA in 181 infected patients, and its relationships with clinical characteristics as well as HBV markers were investigated. Next, we undertook simultaneous deep sequencing of HBV‐RNA/HBV‐DNA and their dynamics among four patients receiving NA therapy who were experiencing viral breakthrough. Results: Serum HBV‐RNA was detected in 25% (31/123) of cases among patients with HBV without NAs, and the detection rate was significantly high in hepatitis B e antigen‐positive cases with high viral activity. In patients with chronic hepatitis, hepatitis B core‐related antigen was significantly correlated with serum HBV‐RNA irrespective of NA use. In the analysis of the four patients experiencing viral breakthrough, no NA resistance mutation was detected in the serum HBV‐RNA immediately before the breakthrough. However, NA‐resistant sequences appeared at the rates of 0%, 3%, 14%, and 100%, and the NA‐resistant HBV‐RNA sequence rate was correlated with the peak HBV‐DNA titer multiplied by the HBV‐DNA detection duration during the breakthrough (R2 = 0.978) observed before redisappearance of HBV‐DNA following the addition of new NA. Conclusion: Serum HBV‐RNA could reflect the transcriptional activity of covalently closed circular DNA and hepatitis B core‐related antigen. The dynamics of HBV‐RNA could help understanding of the turnover process of HBV covalently closed circular DNA in the liver. [ABSTRACT FROM AUTHOR]

Aim: With the current coronavirus disease (COVID‐19) pandemic and high endemic levels of chronic hepatitis B virus (HBV) infection worldwide, it is urgent to investigate liver function changes of COVID‐19 patients with chronic HBV infection, and how severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) infection in turn affects the course of chronic HBV infection. Method: We undertook a retrospective study based on 347 COVID‐19 patients (21 vs. 326 with vs. without chronic HBV infection). With the propensity score matching (PSM) method, we yielded 20 and 51 matched patients for the HBV group and the non‐HBV group, respectively. Results: At the end of follow‐up, all of these 71 patients achieved SARS‐CoV‐2 clearance (P = 0.1). During the follow‐up, 30% versus 31.4% in the HBV group versus non‐HBV group progressed to severe COVID‐19 (P = 0.97). After PSM, the longitudinal changes of median values for liver biochemistries were not significantly different between the two groups. In the HBV group versus non‐HBV group, 35% (7/20) versus 37.25% (19/51) (P = 0.86) had abnormal alanine aminotransferase at least once during hospitalization, 30% (6/20) versus 31.37% (16/51) had abnormal aspartate aminotransferase (P = 0.91), 40% (8/20) versus 37.25% (19/51) had abnormal γ‐glutamyltransferase (P = 0.83), and 45% (9/20) versus 39.22% (20/51) had abnormal total bilirubin levels (P = 0.91). Moreover, three patients in the HBV group had hepatitis B reactivation. Conclusions: Liver dysfunction presented in COVID‐19 patients with/without chronic HBV. Moreover, those COVID‐19 patients co‐infected with chronic HBV could have a risk of hepatitis B reactivation. It is necessary to monitor liver function of COVID‐19 patients, as well as HBV‐DNA levels for those co‐infected with HBV during the whole disease course. [ABSTRACT FROM AUTHOR]

Aim: The artificial liver support system (ALSS) is recognized as a bridge to liver transplantation in hepatitis B virus‐related acute‐on‐chronic liver failure (HBV‐ACLF) patients. However, patient survival remains unknown. We aim to assess the effects of ALSS on survival in HBV‐ACLF patients. Methods: The clinical data of HBV‐ACLF patients receiving standard medical treatment (SMT) plus ALSS (ALSS group, n = 507) or only SMT (SMT group, n = 417) were collected for survival assessment. The main end‐points were cumulative survival rates at days 21, 28, and 90. Four different rigorous analyses were carried out to reduce bias and confounding. Results: In the entire cohort, the cumulative survival rates at days 21, 28, and 90 were significantly higher in patients who underwent ALSS treatment (73.3% vs. 59.6%, 69.2% vs. 56.6%, 56.5% vs. 49.1%, respectively, P < 0.01) than in those who underwent SMT only. In the 276‐pair case–control matched cohort, a significantly higher survival rate was also observed in the ALSS group than in the SMT group on days 21, 28, and 90 (72.5% vs. 60.3%, 68.3% vs. 57.4%, 55.9% vs. 48.5%, respectively, P < 0.05), especially in patients with ACLF‐1 and ‐2. By a multivariable‐adjusted analysis, ALSS treatment was associated with a significantly lower risk of mortality, especially for ACLF‐2 at days 21, 28, and 90. These findings were also confirmed through propensity score matching and inverse probability treatment weighting analysis. Conclusions: ALSS treatment can improve short‐term survival and is associated with a significantly lower risk of short‐term mortality in patients with HBV‐ACLF, especially ACLF‐2. [ABSTRACT FROM AUTHOR]

Aim: This study was designed to investigate the levels of circulating regulatory T cells (Tregs), and their functional subpopulations and related cytokines in chronic hepatitis B patients (CHB) and inactive hepatitis B surface antigen carriers. Methods: The peripheral blood of 24 hepatitis B virus inactive carriers, 26 CHB patients, and 34 healthy controls was collected and analyzed by flow cytometry for Tregs and CD4+CXCR5+FoxP3+ follicular regulatory T cells. Interleukin (IL)‐10, transforming growth factor‐β, and IL‐21 levels in plasma were determined by enzyme‐linked immunosorbent assay. Proportions of functional Treg subpopulations were analyzed by staining of Helios, CD45RA and FoxP3, TIGIT, and CD226, and the correlations between Treg subsets and clinical indicators were explored. Results: CD4+FoxP3+ levels in the peripheral blood of CHB patients were significantly increased, and the inhibitory ability of Tregs in CHB patients for cytokine secretion was stronger, and CD4+CXCR5+FoxP3+ follicular Tregs were also significantly higher than inactive carriers and healthy controls. Transforming growth factor‐β and IL‐10 in the plasma of CHB patients were significantly higher than those of healthy controls, with IL‐21 levels not significantly changed. Circulating CD4+CXCR5‐FoxP3+ Treg cells in CHB patients were positively correlated with hepatitis B surface antigen, hepatitis B e antigen, and hepatitis B virus DNA. The proportions of Helios+FoxP3+, CD45RA–FoxP3hi, and CD226–TIGIT+ functional subpopulations in CD4+CXCR5–FoxP3+ Tregs in CHB patients were significantly increased, and they were significantly correlated with clinical indicators. Conclusions: Circulating Tregs in CHB patients not only have elevated levels, but their follicular Treg subpopulations are also increased, and Tregs tend to have stronger immunosuppressive functions. [ABSTRACT FROM AUTHOR]

Aim: Interferon (IFN)‐λ3 is known to have antiviral effects against various pathogens. Recently, it has been reported that the production of IFN‐λ3 in colon cells after the administration of nucleotide analogs is expected to reduce hepatitis B surface antigen in chronic hepatitis B patients. Here, we aimed to prove the antiviral effects of IFN‐λ3 on hepatitis B virus (HBV) by using an in vitro HBV production and infection system. Methods: We used HepG2.2.15‐derived HBV as an inoculum and the replication‐competent molecular clone of HBV as a replication model. Results: By administering IFN‐λ3 to HepG2 cells transfected with the HBV molecular clone, the production of hepatitis B surface antigen and hepatitis B core‐related antigen was reduced dose‐dependently. IFN‐λ3 treatment also reduced the number of HBV‐positive cells and the synthesis of covalently closed circular DNA after infection of HepG2.2.15‐derived HBV to sodium taurocholate cotransporting polypeptide‐transduced HepG2 cells. The inhibitory effect on HBV infection by IFN‐λ3 was confirmed by using a recombinant a HBV reporter virus system. To elucidate the underlying mechanisms of the anti‐HBV effect of IFN‐λ3, we assessed the transcription of HBV RNA and the production of core‐associated HBV DNA in HBV molecular clone‐transfected HepG2 cells, and found that both parameters were reduced by IFN‐λ3. Conclusions: We observed that the administration of IFN‐λ3 inhibits HBV infection and the production of HBV proteins at the HBV RNA transcription level. This finding provides novel insight into the treatment of chronic hepatitis B patients with the administration or induction of IFN‐λ3. [ABSTRACT FROM AUTHOR]

Aim: A complete cure for chronic hepatitis B virus (HBV) infection requires elimination of covalently closed circular DNA; however, this remains to be clinically achieved. Interferon (IFN)‐γ, a type II IFN, is produced by intrahepatic cytotoxic T lymphocytes and has non‐cytolytic antiviral potential. However, the mechanism by which IFN‐γ regulates HBV infection has not been fully elucidated. Thus, we developed an in vitro HBV infection assay system and analyzed the molecular signature of HBV regulation by IFN‐γ. Methods: The in vitro HBV infection assay system was established in primary human hepatocytes infected with HBV derived from the plasmid containing 1.3‐mer HBV genome, and treated with IFN‐γ. The antiviral effects and signaling pathways of IFN‐γ were examined using microarray, and assessed by siRNA knockdown experiments of the related genes. Results: IFN‐γ treatment suppressed both HBV propagation and transcription as efficiently as IFN‐α. Microarray analysis showed that IFN‐γ stimulation induced the activation of both IFN‐γ and IFN‐α signaling, regulating HBV covalently closed circular DNA. HBV production was decreased by IFN‐γ through Janus kinase/signal transducer and activator of transcription signaling and interferon‐stimulated genes, such as 2′‐5′‐oligoadenylate synthase 2 and apolipoprotein B mRNA editing enzyme catalytic subunit 3G. Conclusions: IFN‐γ can suppress HBV propagation and transcription in hepatocytes by activating specific intracellular signaling pathways in hepatocytes, and suggests the future application of these particular signaling pathways or genes for the complete elimination of HBV. [ABSTRACT FROM AUTHOR]

Aim: Hepatitis B vaccination in infancy was carried out in Japan only when the mother was persistently infected from 1986 to 2016. The aim of the present study was to elucidate the results of vaccination for the prevention of hepatocellular carcinoma in young adults. Methods: We studied the number of patients who had liver cancer and died from 1976 to 2017 using a national database. Furthermore, we carried out a nationwide survey focusing on patients with hepatitis B virus‐related hepatocellular carcinoma who were diagnosed when aged <40 years from 2007 to 2016. Results: The national database showed that the number of deaths of patients aged <40 years decreased from 337 in 1986 to 61 in 2016. Among the 122 patients with hepatocellular carcinoma (HCC) who were registered in the survey, just three patients were born after the start of the vaccination in 1986. Liver cirrhosis, defined by a high Fib‐4 index (≥3.25), was found in just 12.5% of the patients at the time of the survey. HCC was incidentally diagnosed in 85 of the 122 (69%) patients. More than 60% of the patients (54/88) were dead at the time of the study, which may be attributed to the delay in diagnosis. Conclusions: Selective vaccination was effective for the prevention of hepatitis B virus‐related HCC. In contrast, many young adults who missed the chance of hepatitis B vaccination and HCC surveillance developed HCC and died. Hepatitis B virus screening in young adults and careful follow up of infected patients are important to prevent HCC development. [ABSTRACT FROM AUTHOR]

Aim: Entecavir (ETV), tenofovir disoproxil fumarate (TDF), and tenofovir alafenamide (TAF) are first‐line nucleos(t)ide analogues for hepatitis B virus (HBV)‐infected patients. However, consecutive TDF treatment causes renal dysfunction, and the safety and efficacy of TAF have not been established in severe renal dysfunction patients, including hemodialysis patients. The efficacy and safety of ETV in these populations has not been clarified. The study aimed to clarify this. Methods: In this retrospective multicenter study, between 2006 and 2018, a total of 567 HBV‐infected patients treated with ETV monotherapy were screened. Patients were included if >20 years old, treated with ETV monotherapy for >1 year, and had proper clinical information. The efficacy of ETV and changes in renal function were evaluated according to renal function. Results: A total of 273 patients were included: 9.2% (25/273), 1.8% (5/273), and 3.7% (10/273) had chronic kidney disease (CKD) stage G3, CKD stage G4/5, and were on hemodialysis, respectively. Overall, 84.2%, 94.0%, and 96.2% of patients experienced serum HBV‐DNA disappearance at 1, 2, and 3 years, respectively, after treatment initiation. In patients with CKD stage G3–5, estimated glomerular filtration rate tended to restore with time, which was in contrast to patients without renal dysfunction. The rate of disappearance in serum HBV‐DNA, alanine transaminase normalization, and virological breakthrough was similar between patients with or without renal dysfunction. ETV showed high efficacy for all 10 hemodialysis patients without virological breakthrough. Conclusions: Entecavir for HBV‐infected patients with severe renal dysfunction, including hemodialysis patients, is highly effective and does not affect renal function. [ABSTRACT FROM AUTHOR]

Aim: Acute liver injury (ALI) has a favorable prognosis, whereas acute liver failure (ALF) leads to organ failure and thus has an unfavorable prognosis. The effect of each etiology on the clinical course of ALI remains unclear. This study aimed to determine how each etiology and glucocorticoid on the unfavorable etiology affects the clinical course of ALI. Methods: This prospective observational study enrolled 522 patients with ALI/ALF from 2004 and 2017. To evaluate the influence of etiology on prognosis, decision tree analysis was carried out using age, disease type, etiology, and the presence of hepatic encephalopathy. Results: Of 522 patients, 398 patients satisfied the ALI criteria at registration in this study. The ALI etiologies were as follows: viral hepatitis through oral infection (n = 54), acute hepatitis B virus (HBV) infection (n = 24), acute exacerbation of HBV infection (n = 30), de novo hepatitis due to HBV (n = 5), autoimmune hepatitis (n = 59), drug‐induced liver injury (DILI; n = 85), other viruses (n = 12), and undetermined (n = 129). ALI in 46 patients progressed to ALF after registration. Of 11 patients (age >52 years) with ALF due to acute exacerbation of HBV infection or DILI, seven patients (63.6%) died. Whether glucocorticoid affected the clinical course of ALI due to acute exacerbation of HBV infection or DILI was evaluated using propensity score matching (age, sex, alanine aminotransferase, total bilirubin, and prothrombin time‐international normalized ratio). Glucocorticoid did not improve the prognosis of ALI patients due to the two etiologies. Conclusions: Progression of ALI due to DILI or acute exacerbation of HBV infection to ALF showed a poor prognosis. [ABSTRACT FROM AUTHOR]

Aim: We aimed to compare the well‐established liver fibrosis (LF) markers in Japanese patients with chronic hepatitis B (CHB, n = 331) and chronic hepatitis C (CHC, n = 886) and to discuss possible causes of differences in results between CHB patients and CHC patients. Methods: Virtual touch quantification (VTQ) in acoustic radiation force impulse, Fibrosis‐4 (Fib‐4) index, aspartate aminotransferase to platelet ratio index (APRI), and hyaluronic acid (HA) were compared between the two cohorts. As an additional investigation, total collagen proportional area (TCPA, %) was tested using liver pathological samples (n = 83). Results: Significant LF (F2 or greater) and advanced LF (F3 or greater) were identified in 153 (46.2%) and 76 (23.0%) patients in the CHB cohort and 579 (65.3%) and 396 (44.7%) patients in the CHC cohort. The median VTQ, Fib‐4 index, APRI, and HA values in the CHB cohort were 1.20 m/s, 1.36, 0.44, and 25 ng/mL; those in the CHC cohort were 1.32 m/s, 2.60, 0.74, and 65.5 ng/mL (P‐values, all <0.0001). Similar tendencies were noted by F stage‐based stratification. The median TCPA in the CHB cohort and the CHC cohort were 8.5% and 12.7% (P < 0.0006). The TCPA values in the CHC cohort were higher than those in the CHB cohort regardless of LF stage. Conclusion: Values of LF markers in CHB patients can differ from those in CHC patients even in the same LF stage. Difference in total amount of collagen fiber in CHB and CHC appears to be linked to the difference. [ABSTRACT FROM AUTHOR]

Aim: We sought to create a prediction model for intrahepatic covalently closed circular DNA (IH‐cccDNA) level in chronic hepatitis B (CHB) patients and to validate the model's predictive accuracy. Methods: Patients who did not receive previous nucleoside analogue (NA) therapy were assigned to the training cohort (n = 57), and those who received previous NA therapy were assigned to the validation cohort (n = 69). Factors linked to IH‐cccDNA levels in the training cohort were analyzed and a formula to predict IH‐cccDNA levels was constructed. Next, the reproducibility of that formula was assessed. Results: In the multivariate analysis for the prediction of IH‐cccDNA level in the training cohort, fasting blood sugar (FBS) (P = 0.0227), hepatitis B e antigen (HBeAg) (P = 0.0067) and log10(HB surface antigen [HBsAg]) (P = 0.0497) were significant, whereas HB core‐related antigen (HBcrAg) tended to be significant (P = 0.0562). The formula was constructed and named the FBS‐cres score based on the variables used (FBS, HBcrAg, HBeAg, and HBsAg). The FBS‐cres score was calculated as: 3.1686 − (0.0148 × FBS) + (0.1982 × HBcrAg) + (0.0008168 × HBeAg) + (0.1761 × log10(HBsAg)). In the training cohort, a significant correlation was noted between HBcrAg and IH‐cccDNA levels (P < 0.0001, r = 0.67), whereas the FBS‐cres score was more closely correlated to IH‐cccDNA level (P < 0.0001, r = 0.81). In the validation cohort, significant correlation was found between HBcrAg and IH‐cccDNA levels (P = 0.0012, r = 0.38), whereas the FBS‐cres score was more closely linked to IH‐cccDNA levels (P < 0.0001, r = 0.51). Similar tendencies were observed in all subgroup analyses. Conclusion: Our proposed model for the prediction of IH‐cccDNA level could be helpful in CHB patients. [ABSTRACT FROM AUTHOR]

Aim: Flare‐ups of chronic hepatitis B can sometimes be severe and even progress to acute‐on‐chronic liver failure (ACLF), with high short‐term mortality. A timely estimation of the risk of death should be initiated early. The aim of the present study was to determine whether novel biomarkers add prognostic information beyond current clinical scoring systems. Methods: Patients with hepatitis B‐associated ACLF were prospectively enrolled from five hospitals in China between August 2017 and March 2018. Their plasma was screened for soluble CD163 (sCD163), neutrophil gelatinase‐associated lipocalin (NGAL), and copeptin. The association between these biomarkers and mortality was analyzed. The performance of the Model for End‐stage Liver Disease, Asian‐Pacific Association for the Study of the Liver–ACLF Research Consortium score, and the Chronic Liver Failure Consortium ACLF score, with or without biomarkers, were compared. Results: One hundred fifty one patients were enrolled. Advanced ACLF patients had significantly higher levels than early ACLF individuals of plasma biomarkers sCD163 (P = 0.001), NGAL (P = 0.006), and copeptin (P = 0.049). Thirty‐four deaths occurred during the 28‐day follow‐up period (22.5%). Both sCD163 and NGAL showed a strong independent association with 28‐day mortality, whereas copeptin did not. Scoring systems incorporating sCD163 and NGAL had better discrimination and calibration, as measured by area under the receiver operating characteristic curves, the Akaike information criteria, integrated discrimination improvement, and net reclassification improvement. Conclusions: Soluble CD163 and NGAL are independently associated with short‐term mortality in hepatitis B‐associated ACLF. Use of a combination of sCD163 and NGAL improves prognostication. [ABSTRACT FROM AUTHOR]

Aim: Sustained suppression of hepatitis B surface antigen (HBsAg) production after interferon (IFN) treatment has not been reported for children with genotype C chronic hepatitis B virus (HBV) infection, which is prevalent in Asia. Among children with hepatitis B envelope antigen‐positive genotype C chronic HBV infection, we compared the efficacy of combination therapy with nucleotide analogues and IFN‐α in 11 children with 12 historical cases treated with IFN monotherapy. Methods: The combination of lamivudine and conventional IFN‐α was introduced for the first three patients; the other eight patients were treated with entecavir and pegylated IFN. Results: Demographic factors as well as baseline HBsAg titers and HBV‐DNA levels were similar between the two groups. In the combination therapy group, viral loads were suppressed in 9/11 to below 4.0 log copies/mL both at the end of the therapy (EOT) and at 6 months after EOT. In contrast, in the IFN monotherapy group, suppression of viral loads was observed in 2/12 and 3/12 at EOT and at 6 months after EOT, respectively. In the combination therapy group, HBsAg titers dropped from 4.03 at pretreatment to 2.91 log IU/mL at 6 months after EOT with 4/11 showing a drop to below 1000 IU/mL (one patient achieved HBsAg clearance). In contrast, the amount of HBsAg did not change during the corresponding periods in the IFN monotherapy group. Conclusions: Our preliminary results suggest that combination therapy might be effective in the suppression of HBsAg production as well as HBV‐DNA production for children with genotype C chronic HBV infection. [ABSTRACT FROM AUTHOR]

Aim: The consideration of patients' needs in terms of research outcomes is emphasized in research promotion to eradicate hepatitis B virus according to the Basic Act on Hepatitis Measures in Japan. This study analyzed patients' attitudes toward experienced antiviral therapies for chronic hepatitis B and their need for future therapies. Methods: A self‐administered questionnaire comprising 124 questions was completed among patients with chronic hepatitis B from 61 core‐center hospitals designated to implement and research policies on hepatitis in 47 prefectures from August 2013 to January 2014 (n = 3021, response rate = 51%). Results: In decision‐tree models with 333 variables generated from the questionnaire data, patients' satisfaction with therapy and reduction in anxiety about therapy were dependent on favorable therapeutic effects, sufficient information provided by the physician, and fewer lifestyle disturbances. Medical expenses were not selected at a superior branch because subsidy for antiviral therapy started in 2010. In correspondence analysis of free text answers, patients' need for therapy and support mechanisms differed among their attributes, including a great need for novel therapy in older men, hope for avoidance of lifestyle disturbance in younger men, and alleviation of painful experience with the disease in women. Conclusions: Continual provision of sufficient information is necessary to improve the utility of antiviral therapy for chronic hepatitis B as well as for favorable therapeutic effects. The patients believed that novel drugs and support would reduce the diverse burden of the disease on their lives. [ABSTRACT FROM AUTHOR]

Aim: We aimed to identify the incidence rate of hepatocellular carcinoma (HCC) in chronic hepatitis B (CHB) patients treated with entecavir or tenofovir in South Korea, and to identify predictors of HCC development in these patients. Methods: Between January 2007 and December 2015, 582 CHB patients initially received entecavir (n = 406, 69.8%) or tenofovir (n = 176, 30.2%) for CHB. Results: During a median follow‐up of 57.1 months, HCC developed in 38 (6.5%) of the 582 patients, regardless of antiviral agent type. Entecavir‐ and tenofovir‐treated patients had similar HCC development rates (P = 0.471). For the 582 patients, 2‐, 4‐, and 6‐year cumulative HCC development rates were 2.6%, 4.4%, and 8.3%, respectively, and the 2‐, 4‐, and 6‐year cumulative HCC development rates of patients with liver cirrhosis were significantly greater than those of patients without liver cirrhosis (6.2%, 9.8%, and 18.4% vs. 0.3%, 1.1%, and 2.2%, respectively; P < 0.001). Older (≥60 years) patients, regardless of the presence of cirrhosis, and cirrhotic patients aged ≥40 years showed significantly higher risk of HCC development compared to others (both P < 0.05). Multivariate analysis showed that an older age (≥50 years; hazard ratio [HR] 5.02, P = 0.009), and the presence of cirrhosis (HR 4.95, P = 0.002) independently predicted HCC development. Conclusions: The 6‐year cumulative HCC development rate was 6.5% in CHB patients treated with entecavir or tenofovir. Age ≥50 years and liver cirrhosis were found to predict HCC development in these patients. [ABSTRACT FROM AUTHOR]

Aim: The aim of this study was to develop and validate a scoring system to predict the progression to acute‐on‐chronic liver failure (ACLF) in patients with acute exacerbation (AE) of chronic hepatitis B (CHB). Methods: The baseline characteristics of 474 patients with AE of CHB were retrospectively reviewed; 280 and 194 patients were randomly assigned to the derivation and validation cohorts, respectively. Univariate risk factors associated with ACLF development were entered into a multivariate logistic regression. The score model was established, and its predictive value was evaluated by the receiver operating characteristic (ROC) curve and the area under the ROC curve (AUROC). Results: Hepatitis B virus (HBV) DNA, international normalized ratio (INR) of prothrombin time, and patient age were identified as independent risk factors associated with progressing to ACLF. The prediction model was established as R = −13.323 + 0.553 × log HBV‐DNA (copies/mL) + 3.631× INR + 0.053 × age. The AUROCs of our prediction model were higher than those of the Model for End‐stage Liver Disease (MELD) and MELD‐sodium (Na) for both cohorts. At the cut‐off value of −2.43, our prediction model had higher sensitivity (87.5%), specificity (73.6%), positive predictive value (23.0%), positive likelihood ratio (3.30), and lower negative likelihood ratio (0.17) in the validation cohort than those of MELD and MELD‐Na. Conclusion: The independent risk factors associated with progressing to ACLF in patients with AE of CHB are HBV‐DNA, INR, and age. Our risk prediction model is useful for predicting the development of ACLF. [ABSTRACT FROM AUTHOR]

Aim: Autotaxin (ATX) is a secreted enzyme that is considered to be associated with liver damage as well as fibrosis. This study assessed the ability of ATX to diagnose liver fibrosis in patients with chronic hepatitis B virus (HBV) infection. Methods: Serum ATX levels were retrospectively evaluated in 101 treatment‐naïve patients with HBV‐related chronic hepatitis or cirrhosis, all of whom had undergone liver biopsy at our hospital. Results: Serum ATX concentration increased significantly according to liver fibrosis stage in overall (r = 0.46, P < 0.0001), male (r = 0.55, P < 0.0001), and female (r = 0.52, P = 0.0006) patient groups. When analyzed by gender, serum ATX was one of the most reliable markers for all fibrosis stages compared with other tested non‐invasive markers, which included hyaluronic acid, type IV collagen 7S, aspartate aminotransferase‐to‐platelet ratio index, and fibrosis index based on four factors, according to receiver operating characteristic curve analysis. Conclusion: Based on this histologically proven data, ATX represents a novel non‐invasive biomarker for liver fibrosis in HBV‐infected patients. [ABSTRACT FROM AUTHOR]